The cytokines include a large number of mammalian immunoregulatory hormones that are secreted by cells of the immune system. They exert their biological effects through interaction with specific receptors on cell surfaces. Therefore, the biological response to a cytokine is regulated both by the presence of the cytokine and by the expression of its receptor molecule. Many mammalian diseases, including autoimmune, inflammatory and cancer diseases, are correlated with increased or otherwise altered levels of cytokines or cytokine receptors which may contribute to the misregulation of the immune system and to disease progression. Compounds which are capable of blocking the immunoregulatory or inflammatory effects of cytokines should therefore have significant therapeutic activity with respect to such disease states.
Interleukin 6 (IL-6) is a cytokine with pleiotropic biological activities. IL-6 is produced in response to various stimulators in vitro and in vivo and is detectable in serum during acute bacterial infection and inflammatory responses. Among its many different biological effects, IL-6 is required for the terminal differentiation of B cells to immunoglobulin (Ig) secreting cells (Muraguchi, et al., J. Exp. Med. 167:332, 1988) and for the production of acute phase proteins in vitro (Gauldie, et al., Proc. Natl. Acad. Sci. USA 84:7251, 1987) and in vivo (Geiger, et al., Eur. J. Immunol. 18:717, 1988), the latter being characteristic of a systemic reaction to inflammation or tissue injury. IL-6 is also a potent growth factor for myeloma/plasmacytoma cells; it has been shown to induce differentiation of murine myeloid leukemic M1 cells and neoplastic PC12 neural cells, as well as proliferation and differentiation of certain T-cell subsets; and it has been suggested as being a possible mediator of the pathogenesis of Castleman's disease (a syndrome associated with a benign hyperplasia of the lymph nodes) and Lennert's T-cell lymphoma (Kishimoto, Blood 74:1, 1989). IL-6 is detectable in high amounts in synovial fluids of patients with rheumatoid arthritis (Hirano, et al., Eur. J. Immunol. 18:1797, 1988), an inflammatory disease characterized by high levels of Ig secretion and immune complexes. Immune complex-mediated inflammation is also a hallmark of systemic lupus erythematosus in which kidney failure due to immune complex is a leading cause of death. Several tumor cells such as cardiac myxoma and cervical cancer cells (Kishimoto, et al., Ann. Rev. Immunol. 6:485, 1988) have been shown to produce IL-6. Despite considerable sequence differences between mouse and human IL-6, there seems to be no species restriction.
The human IL-6 receptor (IL-6R) has been cloned from the natural killer-like cell line YT (Yamasaki, et al., Science 241:825, 1988). IL-6 receptors are expressed in high numbers on certain tumor cell lines such as human myelomas, histiocytomas and promyelocytic leukemia cells (Taga, et al., J. Exp. Med. 166:967, 1987).
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